Approximately 25% of myocardial infarction (MI) patients progress to develop congestive heart failure, which has a 50% 5-year mortality rate. The goal of this project is to understand post-MI roles of the macrophage by establishing and validating an in silico computational model of the temporal evolution of macrophage polarization. Our preliminary results demonstrate that macrophages proceed through a series of polarization profiles over the first 7 days post-MI and that modifying macrophage polarization can alter remodeling of the left ventricle (LV). We hypothesize that macrophages undergo a temporal phenotype evolution to coordinate the post-MI LV remodeling phenotype. Our specific aims are: 1) construct an in silico computational model that simulates macrophage polarization patterns over the post-MI time course; 2) perturb endogenous IL-1 signaling pathway to evaluate the system and optimize model robustness; and 3) examine exogenous influences to evaluate model predictability. The innovation of this proposal lies in both the concept that macrophages regulate remodeling as a continuum of phenotypes and that integration of experimental and computational approaches will allow us to establish a predictive computational tool. The potential outcome of these studies will be 1) the development of a computational tool to simulate macrophage polarization post-MI; 2) the identification of macrophage polarization markers that predict LV remodeling outcomes; and 3) recognition of key inflammatory mechanisms that can be therapeutically modulated to regulate macrophage polarization.